Enhanced Bimatoprost Ophthalmic Solution

ABSTRACT

A composition comprising from 0.005% to 0.02% bimatoprost by weight and from 100 ppm to 250 ppm benzalkonium chloride, wherein said composition is an aqueous liquid which is formulated for ophthalmic administration is disclosed herein. 
     A method which is useful in treating glaucoma or ocular hypertension related thereto is also disclosed herein.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.11/083,261, filed Mar. 16, 2005, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

This invention relates to pharmaceutical compositions comprisingbimatoprost.

BACKGROUND OF THE INVENTION Description of Related Art

Bimatoprost, shown below, is a prostamide marketed commercially for thetreatment of glaucoma and ocular hypertension.

Benzalkonium chloride (BAK) is a preservative used in many commercialophthalmic products to prevent microbial contamination in multi-useproducts. The commercial eye drops (Bimatoprost, Allergan, Inc., Irvine,Calif.) contain 0.03% bimatoprost and 0.005% BAK. Although no otherprostamides are currently marketed for the treatment of glaucoma,several prostaglandin analogs are commercially available which use BAKas a preservative. These include latanoprost (Xalatan), travoprost(Travatan), and unoprostone isopropyl (Rescula), which requiresignificantly more BAK, from 150-200 ppm, to meet antimicrobialeffectiveness tests in the United States and Europe.

U.S. Pat. No. 6,596,765 B2 discloses a composition comprising 0.005% or0.0005% latanoprost and 0.2 mg/mL BAK.

U.S. Pat. No. 6,646,001 B2 discloses compositions comprising 0.03%bimatoprost and 0.01% BAK or “0.01%+5% excess” BAK.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

FIG. 1 is a plot showing the aqueous humor concentration of the parentacid of bimatoprost after topical administration of severalformulations.

FIG. 2 is a plot showing the membrane permeability of bimatoprost inseveral different formulations.

DETAILED DESCRIPTION OF THE INVENTION

A composition comprising from 0.005% to 0.02% bimatoprost by weight andfrom 100 ppm to 250 ppm benzalkonium chloride, wherein said compositionis an aqueous liquid which is formulated for ophthalmic administrationis disclosed herein.

A method which is useful in treating glaucoma or ocular hypertensionrelated thereto is also disclosed herein.

An aqueous liquid which is formulated for ophthalmic administration isformulated such that it can be administered topically to the eye. Thecomfort should be maximized as much as possible, although sometimesformulation considerations (e.g. drug stability) may necessitate lessthan optimal comfort.

In certain compositions the concentration of bimatoprost is from 0.01%to 0.02%. In other compositions the concentration of bimatoprost is from0.015% to 0.02%.

In certain compositions the concentration of BAK is from 150 ppm to 200ppm. In other compositions the concentration of BAK is from 150 ppm to200 ppm. In other compositions the concentration of BAK is from 150 ppmto 250 ppm.

In ophthalmic compositions, a chelating agent may be used to enhancepreservative effectiveness. Suitable chelating agents are those known inthe art, and, while not intending to be limiting, edetate salts (EDTA)are useful chelating agents.

In certain compositions, concentration of EDTA is at least 0.001%. Inother compositions, the concentration of EDTA is at least 0.01%. Inother compositions the concentration of EDTA is 0.15% or less. In othercompositions the concentration of EDTA is 0.1% or less. In othercompositions the concentration of EDTA is 0.05% or less.

Certain compositions comprise from 150 to 250 ppm BAK and an effectiveamount of EDTA.

As is known in the art, buffers are commonly used to adjust the pH to adesirable range for ophthalmic use. Generally, a pH of around 6-8 isdesired, and in certain compositions a pH of 7.4 is desired. Manybuffers including salts of inorganic acids such as phosphate, borate,and sulfate are known.

Another commonly used excipient in ophthalmic compositions is aviscosity-enhancing, or a thickening agent. Thickening agents are usedfor a variety of reasons, ranging from improving the form of theformulation for convenient administration to improving the contact withthe eye to improve bioavailability. The viscosity-enhancing agent maycomprise a polymer containing hydrophilic groups such asmonosaccharides, polysaccharides, ethylene oxide groups, hydroxylgroups, carboxylic acids or other charged functional groups. While notintending to limit the scope of the invention, some examples of usefulviscosity-enhancing agents are sodium carboxymethylcellulose,hydroxypropylmethylcellulose, povidone, polyvinyl alcohol, andpolyethylene glycol.

In ophthalmic solutions, tonicity agents often are used to adjust thecomposition of the formulation to the desired isotonic range. Tonicityagents are well known in the art and some examples include glycerin,mannitol, sorbitol, sodium chloride, and other electrolytes.

One composition has a pH of 7.4 and consists essentially of 0.015%bimatoprost, 200 ppm benzalkonium chloride, from 0 to 0.03% EDTA, aphosphate buffer, NaCl, and water.

Another composition has a pH of 7.4 and comprises 0.02% bimatoprost, 200ppm benzalkonium chloride, from 0 to 0.03% EDTA, a phosphate buffer,NaCl, and water.

Another composition has a pH of 7.4 and consists of 0.01% bimatoprost,200 ppm benzalkonium chloride, from 0 to 0.03% EDTA, a phosphate buffer,NaCl, and water.

The best mode of making and using the present invention are described inthe following examples. These examples are given only to providedirection and guidance in how to make and use the invention, and are notintended to limit the scope of the invention in any way.

One embodiment comprises 0.01% Bimatoprost, 0.02% Benzalkonium Chloride,0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% Citric Acid,Monohydrate, 0.81% Sodium Chloride, and water, wherein the pH is 7.3.

Another embodiment comprises 0.015% Bimatoprost, 0.02% BenzalkoniumChloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% CitricAcid, Monohydrate, 0.81% Sodium Chloride, and water, wherein the pH is7.3.

Another embodiment comprises 0.015% Bimatoprost, 0.02% BenzalkoniumChloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% CitricAcid, Monohydrate, 0.81% Sodium Chloride, 0.03%, EDTA, and water,wherein the pH is 7.3.

Another embodiment comprises 0.02% Bimatoprost, 0.02% BenzalkoniumChloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% CitricAcid, Monohydrate, 0.81% Sodium Chloride, and water, wherein the pH is7.3.

Another embodiment consists essentially of 0.01% Bimatoprost, 0.02%Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate,0.014% Citric Acid, Monohydrate, 0.81% Sodium Chloride, and water,wherein the pH is 7.3.

Another embodiment consists essentially of 0.015% Bimatoprost, 0.02%Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate,0.014% Citric Acid, Monohydrate, 0.81% Sodium Chloride, and water,wherein the pH is 7.3.

Another embodiment consists essentially of 0.015% Bimatoprost, 0.02%Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate,0.014% Citric Acid, Monohydrate, 0.81% Sodium Chloride, 0.03%, EDTA, andwater, wherein the pH is 7.3.

Another embodiment consists essentially of 0.02% Bimatoprost, 0.02%Benzalkonium Chloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate,0.014% Citric Acid, Monohydrate, 0.81% Sodium Chloride, and water,wherein the pH is 7.3.

Another embodiment consists of 0.01% Bimatoprost, 0.02% BenzalkoniumChloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% CitricAcid, Monohydrate, 0.81% Sodium Chloride, and water, wherein the pH is7.3.

Another embodiment consists of 0.015% Bimatoprost, 0.02% BenzalkoniumChloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% CitricAcid, Monohydrate, 0.81% Sodium Chloride, and water, wherein the pH is7.3.

Another embodiment consists of 0.015% Bimatoprost, 0.02% BenzalkoniumChloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% CitricAcid, Monohydrate, 0.81% Sodium Chloride, 0.03%, EDTA, and water,wherein the pH is 7.3.

Another embodiment consists of 0.02% Bimatoprost, 0.02% BenzalkoniumChloride, 0.268% Sodium Phosphate Dibasic, Heptahydrate, 0.014% CitricAcid, Monohydrate, 0.81% Sodium Chloride, and water, wherein the pH is7.3.

EXAMPLE 1

Formulations containing 0.268% sodium phosphate dibasic heptahydrate,0.014% citric acid, 0.83% sodium chloride, with the pH adjusted to 7.3in qs water, and the amounts of bimatoprost, BAK, and EDTA listed inTable 1 below were prepared by conventional methods well known in theart.

TABLE 1 Formulation 1. 0.03% Bimatoprost (50 ppm BAK) Control 2. 0.03%Bimatoprost - 200 ppm BAK 3. 0.03% Bimatoprost - 0.015% TPGS (nopreservative) 4. 0.03% Bimatoprost - 0.2% TPGS (no preservative) 5.0.03% Bimatoprost - 0.4% TPGS (no preservative) 6. 0.03% Bimatoprost -1.0% TPGS (no preservative)

EXAMPLE 2

Studies were carried out to determine the effect of benzalkoniumchloride (BAK) and d-alpha tocopheryl polyethylene glycol 1000 succinate(TPGS) on ocular absorption of bimatoprost in vivo. For the in vivostudy, eighteen female rabbits were given a single 28 μL eyedropbilaterally and aqueous humor samples were collected (n=3 animals with 6eyes per formulation) at 60 min postdose. Two rabbits (4 eyes) remaineduntreated to serve as pre-dose bioanalytical controls. Bimatoprost andits parent carboxylic acid extracted from aqueous humor and in vitrosamples were analyzed by a liquid chromatography tandem massspectrometry (LC-MS/MS) method with a quantitation range of 0.25-60ng/mL.

Due to extensive metabolism of bimatoprost in rabbit eyes, its parentacid was used as a surrogate for determining ocular absorption ofbimatoprost. Concentration of the acid in rabbit aqueous humor followingsingle dose of 6 different bimatoprost formulations are summarized inFIG. 1 and Table 2 below.

TABLE 2 Formulation Aqueous Humor^(a) (ng/mL) 1. 0.03% Bimatoprost (50ppm 51.0 ± 9.4  BAK) Control 2. 0.03% Bimatoprost - 200 ppm BAK  87.2 ±19.0* 3. 0.03% Bimatoprost - 0.015% TPGS 26.1 ± 3.3* (no preservative)4. 0.03% Bimatoprost - 0.2% TPGS 22.9 ± 3.2* (no preservative) 5. 0.03%Bimatoprost - 0.4% TPGS 19.3 ± 5.6* (no preservative) 6. 0.03%Bimatoprost - 1.0% TPGS 15.4 ± 3.3* (no preservative) ^(a)Mean ± SD. Performulation, N = 3 rabbits (6 eyes). *Statistically different (p < 0.05)compared to 0.03% Bimatoprost

Test formulations containing 0.015%, 0.2%, 0.4% and 1.0% TPGS resultedin a lower aqueous humor carboxylic acid concentration compared toBimatoprost by 52%, 59%, 62% and 72%, respectively. In contrast, 0.03%Bimatoprost containing 200 ppm BAK resulted in 57% higher aqueous humorAGN 191522 concentration compared to Bimatoprost (50 ppm BAK).

While not intending to limit the scope of the invention in any way, orbe bound by theory, compared to the Bimatoprost control, formulationscontaining TPGS resulted in decrease bimatoprost permeability. Incontrast, formulations with higher BAK resulted in higher permeability.

EXAMPLE 3

Formulations containing 0.268% sodium phosphate dibasic heptahydrate,0.014% citric acid, 0.83% sodium chloride, with the pH adjusted to 7.3in qs water, and the amounts of bimatoprost, BAK, and EDTA listed inTable 3 below were prepared by conventional methods well known in theart.

TABLE 3 Formulation A. 0.03% Bimatoprost (50 ppm BAK) - Control B.0.015% Bimatoprost (50 ppm BAK) C. 0.015% Bimatoprost (50 ppm BAK) 0.03%EDTA D. 0.015% Bimatoprost (200 ppm BAK) E. 0.015% Bimatoprost (200 ppmBAK) 0.03% EDTA F. 0.015% Bimatoprost (50 ppm BAK) 0.015% EDTA G. 0.015%Bimatoprost (200 ppm BAK) 0.015% EDTA H. 0.015% Bimatoprost (125 ppmBAK) I. 0.015% Bimatoprost (125 ppm BAK) 0.03% EDTA J. 0.015%Bimatoprost (125 ppm BAK) 0.015% EDTA K. 0.015% Bimatoprost (150 ppmBAK) L. 0.015% Bimatoprost (150 ppm BAK) 0.1% EDTA M. 0.015% BimatoprostN. 0.03% Bimatoprost

EXAMPLE 4

The effect of benzalkonium chloride (BAK) and ethylenediaminetetraaceticacid (EDTA) on bimatoprost permeability across primary culture of rabbitcorneal epithelial cell layers (RCECL). Corneal epithelial cells wereharvested from New Zealand White rabbits and cultured on Transwell™filters until confluency (Day 5). For the transport experiment, cellswere first equilibrated in transport buffer for 1 hour at 37° C. Dosingsolution containing 0.015% or 0.03% bimatoprost with varyingconcentrations of BAK and EDTA was then applied to the apicalcompartment of the Transwell™ (2 cultures; n=3-4 per culture) and thecells were incubated at 37° C. At 30, 60, 90 and 120 minutes postdose,200 μL samples were taken from the basolateral chamber for apical tobasolateral (AB) transport. The samples were analyzed by a liquidchromatography tandem mass spectrometry (LC-MS/MS) method withquantitation range of 1-600 ng/mL.

The results are presented in FIG. 2.

EXAMPLE 5

A drop of formulation J is administered once daily topically to the eyeof a person suffering from glaucoma. After a few hours, intraocularpressure drops more and less hyperemia is observed than would beobserved for formulation A. Lowered intraocular pressure persists for aslong as the treatment continues.

1. A composition comprising from 0.01% to 0.02% bimatoprost by weightand from 100 ppm to 250 ppm benzalkonium chloride, wherein saidcomposition is an aqueous liquid which is formulated for ophthalmicadministration.
 2. The composition of claim 1 which further comprises aneffective amount of EDTA.
 3. The composition of claim 2 wherein theconcentration of benzalkonium chloride is from 150 ppm to 200 ppm. 4.The composition of claim 3 having a pH of 7.4 which consists essentiallyof 0.015% bimatoprost, 200 ppm benzalkonium chloride, from 0 to 0.03%EDTA, a phosphate buffer, NaCl, and water.
 5. The composition of claim 1wherein the concentration of bimatoprost is from 0.01%.
 6. Thecomposition of claim 5 wherein the concentration of bimatoprost is from0.015% to 0.02%.
 7. The composition of claim 6 wherein the concentrationof benzalkonium chloride is from 150 ppm to 200 ppm.
 8. The compositionof claim 7 wherein the concentration of benzalkonium chloride is 200ppm.
 9. The composition of claim 6 which further comprises an effectiveamount of EDTA.
 10. The composition of claim 9 having a pH of 7.4 whichcomprises 0.015% bimatoprost, 200 ppm benzalkonium chloride, from 0 to0.03% EDTA, a phosphate buffer, and NaCl.
 11. The composition of claim10 having a pH of 7.4 which consists of 0.015% bimatoprost, 200 ppmbenzalkonium chloride, from 0 to 0.03% EDTA, a phosphate buffer, NaCl,and water.
 12. A method comprising administering to a mammal sufferingfrom glaucoma or intraocular hypertension a composition comprising from0.01% to 0.02% bimatoprost by weight and from 100 ppm to 250 ppmbenzalkonium chloride.
 13. The method of claim 12 comprising from 0.15%to 0.02% bitmatoprost.
 14. The method of claim 12 comprising 0.01%bitmatoprost.
 15. The method of claim 14 comprising from 0.01% to 0.05%EDTA.
 16. The composition of claim 2 comprising from 150 to 250 ppm BAK.17. The composition of claim 5 comprising 0.01% bitmatoprost, 0.02%benzalkonium chloride, 0.268% sodium phosphate dibasic heptahydrate,0.014% citric acid monohydrate, 0.81% sodium chloride, sufficient sodiumhydride and/or hydrochloric acid to adjust the pH to 7.3, and water.